Acetaminophen (also known as paracetamol, and chemically known as N-(4-hydroxyphenyl)acetamide)) is a widely-used analgesic for the treatment of a variety of conditions related to pain. For example, acetaminophen is used to manage pain from surgery or traumatic injury, and pain produced by chronic inflammatory conditions such as osteoarthritis, rheumatoid arthritis, and lower back pain. In some cases acetaminophen is used to treat pain from mixed nociceptive/neuropathic etiologies, such as cancer or fibromyalgia. Acetaminophen also may have utility in management of other conditions, such as myocardial injury (Spiler N M, Rork T H, Merrill G F; Curr Drug Targets Cardiovasc Haematol Disord. 2005; 5(5):419-29) and nerve injury (Bisaglia M, Venezia V. Piccioli P, Stanzione S, Porcile C, Russo C, Mancini F, Milanese C, Schettini G. Neurochem 2002; 41(1):43-54).
Large quantities of acetaminophen (alone or in combination with other therapeutic agents, such as opioids) are manufactured, prescribed, and distributed throughout the world. With increasing concerns about the cardiovascular and gastrointestinal safety of conventional NSAIDs (such as ibuprofen and naproxen) and selective cyclooxygenase-2 inhibitors such as Vioxx®), patients and physicians have turned to acetaminophen for its seemingly lower safety risks.
However, it is well known that under certain conditions acetaminophen may be toxic to the liver (known as hepatotoxicity). It is estimated that most liver transplants in the United States are caused by acetaminophen toxicity, and 49% of all acute liver failure cases in 2004 were the result of acetaminophen overdose. Each year, overdoses of acetaminophen (sold as Tylenol® and other brands) account for more than 56,000 emergency room visits and an estimated 458 deaths from acute liver failure (Harvard Women's Health Watch, March, 2006). According to a recent study from the U.S. Acute Liver Failure Study Group (Lee W M. Hepatology 2004; 40(1):6-9), acetaminophen-related liver failure appears to be on the rise. Researchers at the University of Washington Medical Center in Seattle found that between 1998 and 2003, the percentage of acute liver failure cases attributed to acetaminophen nearly doubled, rising from 28% to 51%, Acetaminophen toxicity may go beyond liver and may involve kidneys and/or myocardium (J T DiPiro, R L Talbert, G C Yee, G R Matzke, B G Wells, L M Posey (eds) Pharmacotherapy: A Physiological Approach 6th ed McGraw Hill (New York 2005) pp. 133).
Acetaminophen's daily dose limit of 4 grams reduces its therapeutic utility as 4 grains can be consumed in 16 hours (1 gram every 4 hours) leaving the remaining 8 hours of the day to seek alternative analgesics. Further, ethnic and intersubject variability in acetaminophen metabolism have been reported to be as high as 60-fold (S. Bridger, et al. BMJ 1998; 316:1724-1725), which complicates the acetaminophen safety profile as it imparts a high degree of uncertainty in the toxic dose for a given patient. By attenuating toxicity, improved compounds may provide greater utility by allowing doses higher than 4 grams and/or provide a larger safety margin for patients of any ethnic background.
Acetaminophen induced hepatic toxicity has been found to be dependent on both acetaminophen blood level concentration and length of exposure. Consequently, acetaminophen package labels instruct patients to not use the maximum dosage (4000 mg per day) for more than 10 days, and to not take the product for pain for more than 10 days, or for fever for more than 3 days unless directed by a physician. Even healthy adults receiving 4000 mg of acetaminophen per day for 14 days show elevated levels of enzymes indicative of liver toxicity (Journal Amer. Med. Assoc. 296, 87-93, 2006).
It is known that after administration, about 90% of acetaminophen is conjugated with glucuronide and sulphate, and less than 5% remains unmetabolized. The remaining ˜5% of acetaminophen is metabolized in the liver by cytochrome P450 mixed-function oxygenase system (mainly by CYP2E1), and is converted to N-acetyl-p-benzquinone imine (NAPQI) (J T DiPiro, R L Talbert, G C Yee, G R Matzke, B G Wells, L M Posey (eds) Pharmacotherapy: A Physiological Approach 6th ed McGraw Hill (New York 2005) pp. 133). NAPQI is capable of damaging proteins by covalently binding to nucleophilic residues (e.g., cysteine residues). Glutathione (GSH; a tripeptide of L-glutamate, L-cysteine and L-glycine) aids in detoxification by conjugating with NAPQI and may be depleted by as much as 90% following a toxic dose of acetaminophen. Low concentrations of GSH in centrilobular cells of liver can lead to centrilobular hepatic necrosis, which can be fatal (Drug Metabolism and Disposition 31: 1499-1506, 2003). The GSH adduct with NAPQI is either excreted into bile or further metabolized via the mercapturic acid pathway, which involves removal of glutamyl and glycine groups and conversion of cysteine to N-acetylcysteine conjugate. (The Journal of Pharmacology and Experimental Therapeutics 294: 735-745, 2000).
N-acetylcysteine (NAC) also called acetylcysteine (Acetadote®) is an FDA-approved antidote for acetaminophen toxicity available in both oral as well as intravenous dosage form. (Acetadote® package insert. Cumberland Pharmaceuticals, Nashville, Tenn. Issued March 2004.) NAC has been known to prevent or mitigate hepatic toxicity of acetaminophen by stimulating glutathione synthesis (by promoting metabolic pathways) which produces nontoxic metabolites of acetaminophen and/or by detoxifying toxic metabolites (In Goldfrank's Toxicologic Emergencies 7th Ed. New York: McGraw-Hill; 2002, 502-506). However, NAC only has been shown to be effective at minimizing hepatic toxicity when administered within 8-10 hours of acute exposure to toxic blood levels of acetaminophen. Anaphylactoid reactions to intravenously administered NAC have also been reported (Lynch R M, Robertson R. Accid Emerg Nurs. 2004; 12(1):10-5).
Cysteine and methionine (methionine can be converted to cysteine through the hepatic cystathionine pathway) can ensure the maintenance of normal hepatic GSH levels when supplied in adequate amounts. GSH can also be a transport and storage form of cysteine (Journal of Nutrition, 127: 2135-2141, 1997). Extracellular methionine has found to be as strong an antioxidant as cysteine against intracellular reactive oxygen species (Metabolic Bases of Inherited Disease 5th Ed, New York: McGraw-Hill; 1982, 522-559). Oral administration of methionine has been used to treat acetaminophen overdoses, as 30 patients at risk of hepatic damage from acetaminophen ingestion were given 2-5 g oral methionine every four hours up to a total dose of 10 g; where the first dose was given within ten hours of the overdose. There were no deaths and no reports of hepatic encephalopathy or other complications following administration of the methionine (Crome P, Vale J A, Volans G N, Widdop B, Goulding R. Lancet. 1976; 2(7990):829-30). A combination of acetaminophen (500 mg) and methionine (100 mg) is available in the United Kingdom (Paradote®) to prevent the onset of acetaminophen poisoning through the maintenance of high glutathione levels in the liver. The methionine in this formulation contains both the L-isomer (an essential amino acid in humans) and the D-isomer (unnatural). Cysteine and acetylmethionine coupled to acetaminophen have been described in DE 4327462A1 and Skoglund L A, Skjelbred P. Eur J Clin Pharmacol 1984; 26(5):573-7.
Administration of procysteine (L-2-oxothiazolidine-4-carboxylate), which is converted to L-cysteine by 5-oxo-L-prolinase, may result in an increase of intracellular cysteine levels and has been shown to increase GSH synthesis. This effect has been shown to be more pronounced when administered prior to acetaminophen than when administered after acetaminophen (e.g., administration of L-2-oxothiazolidine-4-carboxylate 30 minutes post-acetaminophen administration caused GSH tissue levels to reach 6.1 μmol/g, of tissue compared to 5.3 μmol/g of tissue when administered 120 minutes post-acetaminophen administration; Proceedings of The Natural Academy of Sciences, 79: 6246-6249, 1982).
Some patients (e.g., those with chronic pain) may seek acetaminophen treatment for extended periods to avoid the potentially adverse events of alternative analgesics, such as NSAIDs, selective COX-2 inhibitors, and opioids. Additionally, patients with higher risks for hepatotoxicity (e.g., those with pre-existing liver damage and/or other stressors on the liver, such as alcohol consumption), may still benefit by having access to acetaminophen to control pain and fever.
Accordingly, it would be desirable to provide improved formulations or prodrugs of acetaminophen which address the important problem of hepatotoxicity while maintaining its therapeutic properties and/or which could alter the physicochemical properties of the acetaminophen to allow the development of alternative dosage forms.
The disclosures of all publications, patents, patent applications and other references referred to herein are hereby incorporated herein by reference in their entireties.